2. Hepatits C antiviral agents
Prof. Fatma Amer
Professor of the Microbiology & Immunology, Zagazig Faculty of Medicine, Zagazig, Egypt.

3. Algorithm For HCV Therapy
Wong T , and Lee S (2006). Hepatitis C: a review for primary care physicians. CMAJ; 174 (5):

4. Emerging and future therapy options for HCV
Immune-based therapy
Hepatitis C antiviral agents

5. Two classes of hepatitis C antiviral agents
1. Direct-acting antivirals.
2. Host-targeting antivirals.

6. HCV life cycle and targets for hepatitis C antiviral agents .
Cyclophilin A inhibitors

7. NS3- 4A protease inhibitors
Phase
Target
Company
Drug name
FDA-approved 23/5/2011
NS3-4A serine protease
Vertex / Janssen
Telaprevir 
(VX-950)
FDA-approved 13/5/2011
NS3 protease
Merck (S-P)
Boceprevir 
(SCH503034)
FDA-approved 22/11/2013
NS3/4A protease
Janssen / Medivir
Simeprevir 
(TMC435350) II
Active site / macrocyclic
Roche / InterMune
Danoprevir (R7227)
III
Active site / linear
Boehringer Ingelheim
BI201335
Halted
Schering-Plough
Narlaprevir (SCH900518)
Bristol-Myers Squibb
Asunaprevir 
(BMS ) I
Active site
Phenomix
PHX1766
Gilead
GS-9256

8. Telaprevir (Incivek, Vertex) Boceprevir (Victrelis,
The 1st generation NS3/NS4a protease inhibitors Approved May 2011 by FDA require the addition of the PEG-IFN/RBV backbone
Telaprevir (Incivek, Vertex)
Boceprevir (Victrelis,
Merck)

9. Semiprevir (Olysio) NS3/4A protease inhibitor
FDA approved 22 November 2013
The 1st once-daily protease inhibitor for the treatment of chronic HCV in a combination antiviral regimen

10. Nucleo(t)side analog NS5B polymerase inhibitors
phase
Target
company
Drug name
FDA approved 6/12/2013
NS5B polymerase
Gilead
Sofosbuvir
Stopped
Active site
Idenix / Novartis
Valopicitabine 
(NM283) II
Roche / Pharmasset
Mericitabine (R7128)
Roche
R1626
Pharmasset
PSI-7977
PSI-938
Idenix
IDX184

11. Non-nucleoside NS5B polymerase inhibitors (NNI)
Phase
Target / Active site
Company
Drug name
III
NS3 protease inhibitor
BMS
BMS791325 II
NNI site 1 / thumb 1
Boehringer Ingelheim
BI207127
Merck
MK-3281
NNI site 2 / thumb 2
Pfizer
Filibuvir (PF )
ViroChem Pharma
VCH759
VCH916
VCH222
NNI site 3 / palm 1
Anadys
ANA598
Abbott
ABT-072
ABT-333
NNI site 4 / palm 2
Gilead
GS-9190

12. Presidio Pharmaceuticals
NS5A inhibitor
Phase
Target
Company
Drug name
III
NS5A domain 1 inhibitor
BMS
Daclatasvir 
(BMS ) I
NS5A protein
Bristol-Myers Squibb
BMS
Presidio Pharmaceuticals
PPI-461
Gilead
GS-5885

13. Host-targeting antivirals Cycophilin inhibitors
Phase
Target
Company
Drug name
III
Cyclophilin inhibitor
Debiopharm
Alisporivir 
(Debio-025) I
Cyclophilin inhibitor
Novartis
NIM811 II
Scynexis
SCY-635

14. Characteristics of the Anti-HCV Drug Classes
Genetic Barrier to Resistance
GT Coverage
Potency Against Antiviral Replication
DAA Class
Low
Limited (1)
High
NS3/NS4A protease  inhibitor
+ ribavirin (2, 3) + NS5A inhib (others)
Intermediate
Polymerase inhibitor
NS5B nucleoside
NS5B nonnucleoside
Pangenotypic (1-4)
NS5A replication complex inhibitor
Cyclophilin inhibitors

15. HOT NEWS

16. HCV Antivirals Race to Market
March
Swiss Debiopharm Group announced this week that it has made an exclusive licensing agreement with Novartis to develop and market,
ALISPORIVIR
(Debio 025)

17. SVR in 76% of patients compared with 55% of control.
Phase II study: naïvepatients
with HCV (1, 2, 3, 4)
alisporivir +
pegIFN/RBV
compared with
monotherapy.
SVR in 76% of patients compared with 55% of control.

18. sofosbuvir + daclatasvir
N Engl J Med; January 2014
Once-daily oral
sofosbuvir + daclatasvir
High rates of SVR patients infected with HCV 1, 2, or 3. Including no response to prior telaprevir or boceprevir. .

19. AASLD 64th AASLD Liver Meeting Nov 2013 Washington, DC.
EASL
48th EASL liver Congress
April 2013
Amesterdam

20. Sofosbuvir: the final nail in the coffin for hepatitis C?
Sofosbuvir + Peginterferon + Ribavirin for 12 weeks achieves 90% SVR in genotype 1, 4, 5, or 6 HCV infected patients. (EASL)
Oral regimen sofosbuvir + ribavirin → rapid, consistent antiviral suppression in treatment-naive & -experienced patients with genotype 4. (AASLD 2013)

21. Daclatasvir + Asunaprevir + BMS-791325
(EASL)
IFN/ RBV-Free Regimen
Daclatasvir + Asunaprevir + BMS
Treatment-naive,
HCV (1)
SVR more than 90%

22. Interferon & Ribavirin-Free, Oral Regimen Daclatasvir + Asunaprevir weeks SVR in 85% of Japanese with HCV(1b)
Results Phase 3 BMS's HCV NS5A replication complex inhibitor daclatasvir (BMS ) + the NS3 protease inhibitor asunaprevir (BMS ) → non-responders/ ineligible/intolerant to SCT.
BM seeks Japanese approval
K Chayama, Y Suzuki, K Ikeda, et al. All-oral Combination of Daclatasvir Plus Asunaprevir in Interferon Ineligible Naive/Intolerant and Nonresponder Japanese Patients Chronically Infected with HCV Genotype 1b: Results from a Phase 3 Trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, Abstract211.

23. Getting from A to B to C for treating chronic HCV infection in the next decade.

24. Thank You